Non-alcoholic steatohepatitis (NASH) is a type of non-alcoholic fatty liver disease (NAFLD) that primarily arises in obese and diabetic individuals. About a quarter of people with NASH ultimately develop cirrhosis, which is the main risk factor for hepatocellular carcinoma (HCC). HCC is the second cause of cancer-related mortality worldwide, and HCC associated with NASH is one of the fastest growing causes of cancer-related deaths in the United States, due in large part to the burgeoning obesity and diabetes epidemics. Prevention is, therefore, an urgent unmet need and an important priority to reverse the current trend of increasing incidence in this country. Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors that recognize invading microbes and host-derived (endogenous) damage signaling molecules, playing an important role in the initiation and regulation of innate and adaptive immune responses. They are also involved in the pathogenesis of noninfectious inflammatory diseases of the cardiovascular system, lung, and liver. There are ten functional TLRs in humans (TLR1-10) and twelve in mice (TLR1-9, 11, and 13). Of the known TLR subtypes, TLR4 primarily recognizes lipopolysaccharide (LPS) from gram-negative bacteria. LPS and other ligand binding to TLR4 results in the production of pro-inflammatory molecules such as IL-1, IL-6, IL-10, nitric oxide, and TNF?. TLR4 activation has been shown to enhance TGFb signaling, liver inflammation, and hepatic fibrosis in preclinical models of fibrogenesis, and to aggravate the hepatocellular tumorigenic process in mouse models of alcohol/HCV-associated HCC. Clinically, overexpression of TLR4 in HCC tissues has been associated with poor prognosis in patients with HCC. A recent study has shown that TLR4 deficiency hinders the development of hepatic fibrosis and pre-cancerous liver injury in a mouse model of carcinogenic liver injury. Taken together, these findings indicate that the pharmacologic inhibition of TLR4 signaling may prevent or slow the NASH-associated tumorigenic process. TAK-242 (Resatorvid) is a small molecule developed by Takeda Pharmaceuticals that specifically inhibits TLR4 by binding to Cys747 and disrupting its interaction with adaptor molecules. To date, TAK-242 has only been tested for the treatment of sepsis, but its ability to reduce IL-6, IL-8, and TNF? production in both animal models of sepsis and healthy volunteers challenged with LPS, combined with its demonstrated safety in these studies, makes it a strong candidate for HCC prevention. The purpose of this Task Order is to evaluate TAK-242 for the prevention of HCC associated with NASH.